Coverage of 2006 International
Conference on AIDS

August 14–18, 2006, Toronto, Canada

 

One Entry Inhibitor, One Question Answered

Martin Delaney, Founding Director, Project Inform
August 18, 2006

One concern that has arisen regarding the new class of anti-HIV drugs called entry inhibitors is whether blocking entry through one pathway might cause the virus to shift and use a different pathway. For HIV to enter a CD4+ cell, it usually attaches to the cell at a point known as a receptor. Each receptor has a biological name and the two most common ones are called CCR5 (or R5 for short) and CXCR4 (or X4 for short).

As a general rule, viruses that enter the cell using CCR5 are a bit less active, while those that use X4 tend to be more destructive, causing CD4+ cells to clump together and die in greater numbers. The use of these receptors can change over time in a person, with the CCR5-using virus being more common in early-stage disease and the X4-using virus more common in advanced disease. A virus’ tendency to use one or another receptor is called its tropism. Some people have virus that is R5 tropic, some X4 tropic, and some are dual tropic—meaning they have both types of virus. Many people have both types of HIV, though one or the other is usually dominant, which is called mixed tropism.

This poses an important question about entry inhibitor drugs, particularly those that target CCR5. If the drug succeeds in blocking entry through CCR5, will the virus population shift and switch over to using X4? If it does, might that make things worse for the patient, since the X4 virus is generally more destructive? Clinical trials so far in people with the R5-using virus have not shown many people experiencing a shift to X4, but this only answers half the question. What about people who harbor both types of virus from the start? Will suppressing their R5-using virus just cause their X4 virus to take over?

To test this important question, Pfizer, sponsor of the CCR5 suppressing entry inhibitor called maraviroc, sought out 186 people who were dual tropic. Everyone was assigned to receive what researchers believed was the best possible standard therapy. A portion was given a placebo in addition to this therapy, while other groups received one of two different doses of maraviroc, given either once or twice daily. The main goal of the study was to see whether people receiving maraviroc would experience any harm from blocking the CCR5 receptor and theoretically causing the X4 virus to become dominant.

After 24 weeks, the study showed that most people responded well to therapy, with no evidence of a harmful effect from blocking the CCR5 receptor. The placebo group and the group receiving maraviroc once daily had very similar reductions in viral load of .91 log and .97 log respectively. The group receiving maraviroc twice daily fared a little better with 1.2 log reduction in viral load, but this was not statistically significant. The one surprising finding was that the groups receiving maraviroc either once or twice daily had larger increases in CD4+ cells (59 and 62 cells) than the placebo group (36 cells). This seems to have allayed fears that using the R5 blocking drug would cause a shift toward a virus that destroyed more CD4+ cells. Why this improved CD4+ response occurred in spite of the lack of a significant improvement in viral suppression over the placebo group is unclear.

While these findings are encouraging, it is premature to conclude that this question has been conclusively answered. The numbers of patients in each study were relatively small and the period of follow-up was only 24 weeks. It will be important to follow this or another similar group for a longer time to be certain that no harm comes from treating dual tropic patients with a R5 inhibitor. Before this study, it was believed that patients might need to be tested for their viral tropism before taking the R5 inhibitor, in order to screen out people who were dual or mixed tropic. This study suggests that this will not be necessary. The FDA will be the final judge though as to whether this single, modestly sized and fairly short study is sufficient to eliminate concerns over tropism shift.

It is also fair to note a little disappointment that in this study: the addition of maraviroc did not result in much of an improvement compared to the standard therapies that everyone received. The added impact on viral load was negligible and the only positive finding was a gain of a bit fewer than 30 extra CD4+ cells. In its defense, the company points out that the study wasn’t designed to test the drug’s efficacy in the advanced patient population and that they have other studies under way which will answer the question of efficacy. Fair enough, but it still was logical to expect a somewhat better suppression of virus than was shown here.